Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: An interrupted time-series analysis

Oral third-generation cephalosporins (3GCs) are not recommended for use owing to their low bioavailability and the risk of emergence of resistant microorganisms with overuse. A standardized and effective method for reducing their use is lacking. Here, in a 60-month, single-institution, interrupted time-series analysis, which was retrospectively conducted between April 1, 2017, and March 31, 2022, we evaluated the effectiveness of a four-phase intervention to reduce the use of 3GCs in patients at a cancer center: Phase 1 (pre-intervention), Phase 2 (review of clinical pathways), Phase 3 (establishment of infectious disease consultation service and implementation of antimicrobial stewardship program), and Phase 4 (educational lecture and pop-up displays for oral antimicrobials at the time of ordering). Although no significant changes were observed in Phases 3 and 4, the first intervention resulted in a significant decrease in the trend and level of days of therapy (DOT) for 3GCs. The level for cephalexin DOT and the trend for sulfamethoxazole-trimethoprim DOT increased in Phase 4, and the trend for amoxicillin and amoxicillin-clavulanate DOT increased in Phase 3. Macrolide DOT showed a decreasing trend in Phases 2 and 4 and decreasing and increased levels in Phases 3 and 4, respectively; no change was observed for quinolones. Actual and adjusted purchase costs of 3GCs decreased significantly during all study periods, while those for oral antimicrobials decreased in Phase 2, and actual purchase costs increased in Phases 3 and 4. No significant reduction in resistant organisms, length of hospital stay, or mortality was observed. This is the first study on the effects of oral 3GC reduction strategies in patients with cancer. We conclude that even facilities that substantially use antimicrobials can efficiently reduce the use of 3GCs.


Interventions for reducing the use of oral 3GCs
The intervention evaluated in this study was implemented in four phases: Beginning in June 2019, cefdinir was removed from the orthopedic perioperative clinical pathway, and cefditoren was removed from the hospital's list of adopted drugs.
Phase 3: Establishing an ID consultation service and implementing ASP (April 1, 2020, to June 30, 2021) The ID consultation and ASP were introduced on April 1, 2020. The ID consultation service is a system in which, for 5 days per week, full-time ID physicians provide ID consultation for referrals from the other 15 departments, review positive blood culture results to ensure that patients receive the appropriate empirical treatment, and provide feedback to other physicians. The ASP was structured as follows: for 3 days per week, the antimicrobial stewardship team evaluated medical records and antimicrobial use for patients who were administered specific intravenous broad-spectrum antibiotics (vancomycin, teicoplanin, daptomycin, linezolid, cefepime, cefozopran, piperacillin-tazobactam, imipenem-cilastatin, meropenem, and doripenem) and provided post-prescription review with feedback to the physician (changed to 5 days per week from April 2021 and addition of intravenous levofloxacin). In October 2020, cefdinir was removed from the list of drugs adopted in hospitals.
Phase 4: Educational lecture and pop-up displays for oral antimicrobials (July 1, 2021, to March 31, 2022) Lectures on oral antimicrobial agents were conducted for all healthcare professionals, including physicians, nurses, and pharmacists, between July 1, 2021 and July 31, 2021, with a 100% attendance rate. From November 1, 2021, a pop-up was displayed on the electronic medical record when prescribing third-generation oral antimicrobials ( Table 1).

Primary outcome measures
The primary outcome measured was the change in days of therapy (DOT) with oral 3GCs (3GCs-DOT; for cefdinir, cefcapene, and cefditoren), expressed as DOT per 100 patient-days per month.

Secondary outcome measures
DOT for cefalexin, amoxicillin, amoxicillin-clavulanate, and sulfamethoxazole-trimethoprim. The total DOT per month per 100 patient-days was calculated for the four antimicrobial agents cefalexin (first-generation cephalosporin), amoxicillin, amoxicillinclavulanate, and sulfamethoxazole-trimethoprim, as these antibiotics are narrow-spectrum antimicrobials. This parameter was assessed to confirm whether the intervention was performed appropriately.
DOT for quinolones and macrolides. The total DOT per month per 100 patient-days was calculated for three quinolones (moxifloxacin, ciprofloxacin, and levofloxacin) and three macrolides (erythromycin, azithromycin, and clarithromycin). This was because these antibiotics are broad-spectrum antimicrobials, similar to 3GCs. The DOT for quinolones and macrolides was evaluated to assess whether 3GCs were simply being replaced with other broad-spectrum agents.

Incidence of hospital-acquired infection with resistant microorganisms and C. difficile
We measured the annual incidence of infections with antibiotic-resistant bacteria and C. difficile infection (CDI) per 1000 patient-days between April 2017 and March 2022, the period for which these data were available, as an indicator of the outcome of our interventions. The resistant microorganisms included ESBL-producing Enterobacteriaceae, PRSP, and resistant Haemophilus influenzae. Hospital-acquired microorganisms were defined as those that were identified more than 72 h after admission [25]. To exclude duplication, when the same resistant microorganisms were isolated more than once in the same patient, only the first specimen obtained each month was included in the analysis [25]. However, if the resistant microorganism was detected in a blood specimen, this infection was defined as a new episode if the same resistant bacterium had not been detected in blood samples from the same patient within the previous two weeks [25]. Only clinical specimens of resistant microorganisms were included, and specimens for surveillance culture and negative confirmation were excluded. CDI was defined as the number of patients with positive CD toxin results (C. DIFF QUIK CHEK COMPLETE; Alere Medical Co., Tokyo, Japan Oral third-generation cephalosporins are not recommended due to their low bioavailability, as well as problems with drug-resistant bacteria. Please consider switching to another drug. Examples of switching to other drugs: 1) Oral switch from cefazolin: cefalexin 2) Oral switch from ampicillin-sulbactam or cefmetazole: amoxicillin-clavulanate 3) Empirical treatment for cystitis: cefalexin or sulfamethoxazole-trimethoprim If you have any questions about oral antimicrobial prescription, please contact the Department of Infectious Diseases. https://doi.org/10.1371/journal.pone.0281518.t001

Cost of 3GCs and all oral antimicrobials
To assess the economic impact of our interventions, we assessed the cost of purchasing antimicrobials per patient-day each year from April 2017 to March 2022 and April 2018 to March 2021. The exchange rate of 1 USD to 108 JPY was used for the calculations in March 2021.

Total number of inpatient specimens
To assess the influence of the total number of specimens on the detection of resistant organisms, we evaluated the total number of inpatient specimens per 100 patient-days from April 2017 to March 2022.

All-cause in-hospital mortality and length of hospital stay
Data for all-cause in-hospital mortality and length of hospital stay were extracted and included in the analysis.

Statistical analysis
To demonstrate the effect of each intervention on 3GCs-DOT, the DOT for cefalexin, amoxicillin, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, the three quinolones (moxifloxacin, ciprofloxacin, and levofloxacin), and the three macrolides (erythromycin, azithromycin, and clarithromycin) was calculated. Furthermore, we carried out a segmented regression analysis of interrupted time-series studies for the four periods (Phase 1: April 1, 2017, to May 31, 2019; Phase 2: June 1, 2019, to March 31, 2020; Phase 3: April 1, 2020, to June 30, 2021; Phase 4: July 1, 2021, to March 31, 2022), when DOT data were available. Trends and changes in the levels of incidence of antibiotic-resistant bacterial infection, CDI, all-cause inhospital mortality, and length of hospital stay were evaluated using a segmented regression analysis of interrupted time-series studies for two periods (Phase 1, Phases 2-4). We adopted a linear regression model with the Prais-Winsten estimator using Generalized Least Squares. Seasonality was not statistically confirmed to affect the primary outcome. This model was also used for all secondary outcomes. Bivariate analysis for the cost of antimicrobials was carried out using the Mann-Whitney U test (continuous variables), with p < 0.05 regarded as statistically significant. The R software, version 4.0.2. (The R Foundation for Statistical Computing, Vienna, Austria) was used for all analyses.

Ethical considerations
This study was approved by the Institutional Review Board of the ACC Hospital (approval number: 2021-0-176) and conducted according to the principles of the Declaration of Helsinki. The requirement of informed consent was waived because this study only used data that were collected in clinical practice.

Use of 3GCs
Changes in 3GCs-DOT during the four phases are shown in Fig 1. After initiation of the first intervention, the monthly 3GCs-DOT showed a decreasing trend (coefficients: -0.08; 95% confidence interval [CI]: -0.15 to -0.01, p < 0.05) and the level of the monthly 3GCs-DOT also reduced (coefficients: -0.5; 95% CI: -0.93 to 0.03, p < 0.05). There were no significant changes in trends and levels from Phases 2 to 3 or from Phases 3 to 4.

Use of cefalexin, amoxicillin, amoxicillin-clavulanate, and sulfamethoxazole-trimethoprim
There were no significant changes in trends and levels for cephalexin from Phases 1 to 2 or from Phases 2 to 3. The trend in the monthly DOT of cephalexin did not change from Phases 3 to 4, but the level increased (coefficients: 0.42; 95% CI: 0.03 to 0.81, p = 0.04; Fig 2).
There were no significant changes in the trend and level of the monthly DOT of amoxicillin and amoxicillin-clavulanate from Phases 1 to 2 (Fig 3). The trend in the monthly DOT of amoxicillin and amoxicillin-clavulanate increased from Phases 2 to 3 (coefficients: 0.26; 95% CI: 0.07 to 0.45, p = 0.01) and decreased from Phases 3 to 4 (coefficients: -0.67; 95% CI: -0.89 to -0.45, p < 0.001), while the level did not change.
The trend and level of the monthly DOT of sulfamethoxazole-trimethoprim did not change significantly from Phases 1 to 2 or Phases 2 to 3 (Fig 4). However, the trend in the monthly DOT of sulfamethoxazole-trimethoprim increased from Phases 3 to 4 (coefficients: 0.26; coefficient: 0.38; 95% CI: 0.07 to 0.70, p = 0.02), while the level did not change.

Use of quinolone and macrolide
The trend and level of the monthly DOT of all three quinolones (moxifloxacin, ciprofloxacin, and levofloxacin) did not change significantly during the study period (Fig 5).

Incidence of infection with antimicrobial-resistant microorganisms and CDI
The trend and level of the monthly incidence of ESBL-producing Enterobacteriaceae, PRSP, resistant H. influenzae and CDI did not change significantly during the study period (Figs 7-10). The trend in the monthly incidence of methicillin-resistant Staphylococcus aureus (MRSA) increased during the study period (coefficients: 0.05; 95% CI: 0.04 to 0.07, p < 0.001), but the level did not change (Fig 11). Table 2 shows the actual and adjusted average costs of 3GCs and all oral antimicrobials. The actual (Phase 1 to 2: p < 0.001; Phase 2 to 3: p < 0.01, Phase 3 to 4: p < 0.001) and adjusted 3GC purchase costs (Phase 1 to 2: p < 0.001; Phase 2 to 3: p < 0.01, Phase 3 to 4: p < 0.01) per patient-days significantly decreased during the study period. The actual purchasing cost of all oral antimicrobials per patient-day decreased significantly from Phases 1 to 2 (p < 0.01) but increased from Phases 2 to 3 (p < 0.01) and from Phases 3 to 4 (p = 0.01). The adjusted purchase cost of all oral antimicrobials per patient-day decreased significantly from Phases 1 to 2 (p < 0.001) but did not change from Phases 2 to 3 (p = 0.18) or from Phases 3 to 4 (p = 0.29).

Total number of inpatient specimens
The number of inpatient samples per 100 patient-day did not change from Phases 1 to 2 (median: 5.05 vs. 4.85, p = 0.412) but increased from Phases 2 to 3 (median: 4.85 vs. 6.46, p < 0.001). There was no change in the number of inpatient samples in Phases 3 to 4 (median: 6.46 vs. 6.95, p = 0.07).

All-cause in-hospital mortality and length of hospital stay
There was no significant change in the trend of in-hospital mortality, length of hospital stay, or their level (Figs 12 and 13).

Discussion
The present study is the first to report the effects of an oral 3GC reduction strategy in patients with cancer. It is difficult to provide comprehensive interventions in cancer centers owing to  the complexity of patient conditions caused by underlying cancers, hematological malignancies, neutropenia, various departments involved in multidisciplinary patient management, departmental structures, and internal guidelines [28]. In addition, the use of antimicrobials is higher among patients with cancer than among the general population [3,4]. However, even  in a population of patients with cancer and high antimicrobial use, each of our interventions contributed to a reduction in the use of oral 3GCs without worsening patient outcomes or increasing the use of alternative broad-spectrum antimicrobial agents and decreased the overall cost of oral antimicrobial agents.
In the current study, 3GCs showed a significant decrease in trends and levels with the clinical path review (Phase 2). Subsequently, both trends and levels showed a decline, but not significantly. This finding suggested that Phases 3 and 4 maintained the intervention effects from Phase 2 and implied that the mandatory intervention of clinical path review had a significant impact on the overall 3GC reduction. The level of monthly DOT of cephalexin increased from Phases 3 to 4. This finding was attributed to the educational lecture and pop-up displays. From Phases 2 to 3, the trend in the monthly DOT for amoxicillin and amoxicillin-clavulanate increased, which was considered an effect of ID consultation and ASP. The increase in the cephalexin, amoxicillin, and amoxicillin-clavulanate DOT indicated appropriate antimicrobial use. Furthermore, for trimethoprim-sulfamethoxazole, the trend increased from Phases 3 to 4, but the trend and level were not consistent during the study period. Patients with cancer are treated with substantial amounts of glucocorticoids as antiemetics during chemotherapy to  treat immune-related adverse events associated with immune checkpoint inhibitors and druginduced pneumonia. This is a high-risk factor for Pneumocystis jirovecii pneumonia and a possible reason for the frequent use of trimethoprim-sulfamethoxazole for its prevention and treatment in our cancer center [29]. The monthly DOT for macrolides showed a decreasing trend from Phases 1 to 2 and 3 to 4, and the level decreased from Phases 2 to 3. The change  from Phases 2 to 3 was believed to be due to the impact of ID consultation and ASP, supporting the appropriate use of antimicrobials. Macrolides are commonly used for the treatment of atypical pneumonia, non-tuberculous mycobacterial infections, and sexually transmitted infections, but our hospital had few cases of these infections, and most of them were considered inappropriate for macrolide treatment. These findings for macrolide use during the study period were a favorable outcome, as they indicated that no switch was made from oral 3GCs. There was no change in the use of quinolone during the study period, implying that a simple switch from oral 3GCs did not occur. The use of quinolones could be attributed to their constant use in the treatment of low-risk febrile neutropenia [30] and to some physicians who do not follow the recommendations of ID physicians and antimicrobial stewardship teams.
The main concept of appropriate antimicrobial use in any patient population, including patients with cancer, is to ensure that each patient receives the most effective and safest antimicrobial agents for the treatment of infections, while simultaneously minimizing the impact on the ecosystem [31]. Patients with cancer have a high incidence of infections and require the use of antimicrobials for both treatment and prophylaxis, resulting in a significant amount of antimicrobial use [28]. This imposes significant antimicrobial pressure not only on the normal microflora of patients but also on the surrounding environment. The present study showed a significant reduction in the use of oral 3GCs without an increase in alternative broad-spectrum oral antimicrobials, but not the use of ESBL-producing Enterobacteriaceae, PRSP, BLNAR, CDI, or MRSA. A single-center study by Uda et al. showed that a reduction in the use of oral 3GCs did not reduce the incidence of PRSP and BLNAR, which is consistent with our current findings [21]. Similarly, Kato et al. showed that a reduction in the use of oral 3GCs did not change the incidence of ESBL-producing Enterobacteriaceae, MRSA, or AmpC beta-lactamase-producing bacteria [32]. There may be no association between the use of oral 3GCs and the incidence of these resistant organisms. However, the incidence of these resistant organisms in the pre-intervention period was most likely underestimated because the total number of hospitalized patient specimens in the current study increased significantly after the intervention. Our intervention did not result in significant changes in in-hospital mortality or length of stay, suggesting that it is safe and does not negatively impact patient outcomes. As these were single-center studies, future investigation is necessary to determine whether reducing the consumption of 3GCs in the community will reduce the prevalence of resistant microorganisms or improve patient outcomes.
Our intervention led to a reduction in the cost of 3GCs and the cost of adjusted purchases of all oral antimicrobials, which has economic benefits. The actual cost of purchasing all oral antimicrobials decreased significantly after the clinical path review but increased subsequently. This finding was most likely the result of increased appropriate use of alternative antimicrobial agents.
It is challenging to change the antimicrobial-prescribing behavior of physicians for several reasons: physicians tend to disregard the seriousness of preventing the development of resistant bacteria, and knowledge outside the physician's field of expertise does not appear to be updated [24]. Prospective audit and feedback of antimicrobials are effective but time-consuming [3], and intervention is often difficult because oral antimicrobials are already prescribed as a discharge prescription. The number of ID physicians in Japan is inadequate compared to that in the United States [3]. Furthermore, the training of ID physicians, pharmacists, laboratory technicians, and infection-control nurses in cancer centers is often time-consuming, given the complex background of patients with cancer, which requires sufficient experience and knowledge of ID and oncology. However, review of clinical pathways, educational lectures, and pop-up displays at the time of prescribing oral 3GCS may be relatively easy to address even in the absence of experts.
There are several limitations to this study. First, it is a single-center study in a Japanese cancer center; therefore, it is unclear whether a hospital-based oral 3GC reduction strategy can be generalized. As such, a long-term multicenter study including other Japanese cancer centers is warranted. However, the positive results at our institution, with its high antimicrobial-prescribing and large number of immunocompromised patients (patients with cancer) are likely to be adaptable to other hospitals. Second, the impact of antimicrobial prescriptions on patients with coronavirus disease (COVID-19) and hospitalized patients with suspected COVID-19 during the pandemic needs to be considered [33]. This is because antimicrobials have been used both prophylactically and therapeutically in such patients [33,34]. That said, our hospital was affected by the COVID-19 pandemic, but the prescription of 3GCs showed a decline.
In conclusion, this is the first study to report on the impact of an oral 3GC reduction strategy in patients with cancer. We conducted a clinical path review, implemented an ID consultation and ASP, and provided educational lectures and pop-up displays at a cancer center in Japan. Our intervention reduced the use of oral 3GCs without worsening patient outcomes or increasing the use of alternative broad-spectrum antimicrobials and reduced the overall cost of oral antimicrobials. Overall, our strategy indicates that even facilities which use antimicrobials substantially can efficiently and easily reduce the use of 3GCs.